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Medicine

OBSERVATIONAL STUDY

Infant Stool Color Card Screening Helps Reduce the


Hospitalization Rate and Mortality of Biliary Atresia
A 14-Year Nationwide Cohort Study in Taiwan
Min Lee, MD, Solomon Chih-Cheng Chen, MD, PhD, Hsin-Yi Yang, PhD, Jui-Hua Huang, PhD,
Chun-Yan Yeung, MD, and Hung-Chang Lee, MD

Abstract: Biliary atresia (BA) is a significant liver disease in children. increase in the risk for both LT (hazard ratio [HR] 1.14, 95%
Since 2004, Taiwan has implemented a national screening program that confidence interval [CI] 1.101.18) and death (HR 1.05, 95%
uses an infant stool color card (SCC) for the early detection of BA. The CI 1.011.08) for each additional hospitalization. A multivariate
purpose of this study was to examine the outcomes of BA cases before logistic regression model found that cases with a Hosp/2yr >6 times
and after the launch of this screening program. The objectives of this had a significantly higher risk for both LT (adjusted odds ratio
study were to evaluate the rates of hospitalization, liver transplantation [aOR] 4.35, 95% CI 2.826.73) and death (aOR 1.75, 95%
(LT), and mortality of BA cases before and after the program, and to CI 1.172.62).
examine the association between the hospitalization rate and survival The hospitalization and mortality rates of BA cases in Taiwan were
outcomes. significantly and coincidentally reduced after the launch of the SCC
This was a population-based cohort study. BA cases born during screening program. There was a significant association between the
1997 to 2010 were identified from the Taiwan National Health Insurance hospitalization rate and final outcomes of LT or death. The SCC
Research Database. Sex, birth date, hospitalization date, LT, and death screening program can help reduce the hospitalization rate and mortality
data were collected and analyzed. The hospitalization rate by 2 years of of BA cases and bring great financial benefit.
age (Hosp/2yr) was calculated to evaluate its association with the (Medicine 95(12):e3166)
outcomes of LT or death.
Among 513 total BA cases, 457 (89%) underwent the Kasai Abbreviations: BA = biliary atresia, CI = confidence interval, HR
procedure. Of these, the Hosp/2yr was significantly reduced from 6.0 = hazard ratio, ICD-9-CM = International Classification of
to 6.9/case in the earlier cohort (19972004) to 4.9 to 5.3/case in the Diseases, Ninth Revision, Clinical Modification, LT = liver
later cohort (20052010). This hospitalization rate reduction was transplantation, NHIRD = National Health Insurance Research
followed by a reduction in mortality from 26.2% to 15.9% after Database, OR = odds ratio, SCC = stool color card.
2006. The Cox proportional hazards model showed a significant

Editor: Mostafa Sira. INTRODUCTION


Received: January 22, 2016; revised: February 22, 2016; accepted:
February 24, 2016.
From the Department of Pediatrics (ML), Taipei City Hospital, Zhongxiao
Branch, Taipei City; Department of Medical Research (SC-CC, H-YY,
B iliary atresia (BA), an idiopathic obliteration of the biliary
ductal system, is a common cause of liver transplantation
(LT) or death from liver disease in infants or children.1 The best
J-HH), Ditmanson Medical Foundation Chia-Yi Christian Hospital, Chiayi outcomes are highly correlated with an early diagnosis and
City; Department of Pediatrics (SC-CC), School of Medicine, Taipei
Medical University, Taipei; Department of Pediatrics (C-YY), MacKay surgical treatment.15 The Kasai procedure (hepatoportoenter-
Childrens Hospital, Taipei City; and MacKay Memorial Hospital (H-CL), ostomy) is the primary surgical therapy for BA.2 Increased age
Hsinchu Branch, Hsinchu City, Taiwan. at the time of the Kasai procedure may result in a progressive
Correspondence: Solomon Chih-Cheng Chen, Department of Pediatrics, and sustained deleterious effect on the outcomes of BA cases.35
Ditmanson Medical Foundation Chia-Yi Christian Hospital, No. 539,
Zhongxiao Rd., East District, Chiayi 60002, Taiwan Therefore, reducing the age at which children undergo the Kasai
(e-mail: solomon.ccc@gmail.com). procedure is an important method to improve the outcomes of BA
This study was based in part on data from the National Health Insurance cases.2,57 Our previous paper found that the Kasai procedure
Research Database (NHIRD) provided by the Bureau of National Health performed at a younger age may reduce the need for LT. The
Insurance of the Department of Health and Welfare and managed by the
National Health Research Institutes. The interpretation and conclusions LT rates were 25.6% and 32.3% in patients who received
contained within do not represent those of the Bureau of National Health the Kasai procedure within 60 days or after 60 days of age,
Insurance, the Department of Health and Welfare or the National Health respectively.8
Research Institutes. Because Taiwan has a National Health Insurance system
This study was supported by the Ditmanson Medical Foundation Chia-Yi
Christian Hospital Research Program (R102-11). The sponsor had no with high (almost 99%) coverage of the entire population, we
role in the study design; the collection, analysis, and interpretation of were able to examine the national inpatient records of BA cases
data; the writing of the report; and the decision to submit the paper for based on the National Health Insurance claims data set. Based
publication. on this data set, our previous study found that there was a
The authors have no conflicts of interest to disclose.
Supplemental Digital Content is available for this article. decreasing trend in age at diagnosis and surgery in BA cases.
Copyright # 2016 Wolters Kluwer Health, Inc. All rights reserved. The mean ages at diagnosis were 57.9, 55.6, and 52.6 days in
This is an open access article distributed under the Creative Commons 1997 to 2001, 2002 to 2006, and 2007 to 2011, respectively.
Attribution License 4.0, which permits unrestricted use, distribution, and In addition, the proportion of BA cases that received the
reproduction in any medium, provided the original work is properly cited.
ISSN: 0025-7974 Kasai procedure within 60 days of age gradually increased
DOI: 10.1097/MD.0000000000003166 from 76% to 81%.8

Medicine  Volume 95, Number 12, March 2016 www.md-journal.com | 1


Lee et al Medicine  Volume 95, Number 12, March 2016

To detect BA cases earlier, Taiwan initiated a universal based on the number of hospitalizations per case until 2years of
screening program in 2004 that involves using an infant stool age (Hosp/2yr). The sensitivity and specificity of the cutoff
color card (SCC).912 The SCC is placed within the Child Health values for survival outcomes in BA patients were calculated. A
Handbook that is provided for every newborn. When infants are multivariate logistic regression analysis was further performed
brought to hospitals or clinics for vaccinations at the first 2 months to identify the risk factors for LT, death, and either LT/death in
of age, their parents or guardians will be asked for the infants BA patients. The sex, birth cohort (19972004 or 20052010),
stool color. If a discolored stool is suspected, the infants are age at the Kasai procedure (>60 or 60 days), and Hosp/2yr
referred to a pediatric gastroenterologist for further workup. (>6 or 6 times) were entered together into a multivariate
Because the SCC screening program is a feasible, cost-effective, logistic regression analysis. All of the statistical procedures
and beneficial strategy for BA detection,1214 it has currently were performed using SPSS for Windows version 21.0 (SPSS;
been applied regionally or nationally in some countries including IBM Corporation, Somers, NY), and a P  0.05 or less was
Brazil, Japan, Switzerland, Canada, and the Netherlands.1318 considered statistically significant. The ROC curve computing
The aim of this study was to examine whether the imple- and graphics were performed using R, version 3.2.1, with the
mentation of the SCC screening program can improve BA case Epi packages.
outcomes. The objectives of this study were to assess the
hospitalization, LT, and mortality rates of BA cases before RESULTS
and after the launch of this screening program, and (2) to
examine the association between the hospitalization rate and The Incidences of BA Cases
survival outcomes. There were a total of 513 BA cases identified between
1997 and 2010. The incidence of BA ranged between 0.12 and
MATERIALS AND METHODS 0.19 per 1000 live births, and did not display a specific trend
during the observational period (P 0.682). Among the BA
Ethical Approval and Data Resource cases, 457 (89%) had received the Kasai procedure. The
The Taiwan National Health Insurance Research Database operation rate did not change significantly during the study
(NHIRD) is a nationwide, population-based reimbursement period (P 0.904). Approximately one-fourth to one-third of
database designed for research. The identification numbers of BA cases underwent the Kasai procedure after the age of 60
all persons and hospitals in this database were encrypted to be days; this proportion was without significant trend (P 0.251).
unrecognizable from the original identification numbers. Thus,
this study represents de-identified secondary data. The Institu- Trends in the Hospitalization Rate and Length of
tional Review Board of our institution waived the requirement Stay
for written informed consent from the patients and approved this The average and standard deviation of operation age, the
study (CYCH-IRB No. 102023). proportion of cases undergoing the operation after 60 days of
age, the average Hosp/2yr, and the length of stay (LOS) per
Case Identification and Incidences hospitalization are summarized in Table 1. The average Hosp/
Following the criteria of previous studies,8,19,20 we ident- 2yr was 4.9 to 6.9 times, and it was significantly reduced after
ified BA cases on the basis of the International Classification of 2004, displaying a decrease from 6.0 to 6.9 times in the earlier
Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) cohort (19972004) to 4.9 to 5.3 times in the later cohort
code for BA (751.61) plus either the Kasai procedure (ICD-9- (20052010). However, the LOS of each hospitalization was
CM code 51.37) or LT (ICD-9-CM code 50.5) from Taiwans approximately 76 and 88 days for the earlier and later cohorts,
NHIRD during 1997 to 2010. We collected and analyzed data on respectively, which did not differ significantly (P 0.432).
the sex, birth date, and date of each hospitalization and oper-
ation from the database. The BA cases from every 2 years were
Trends of Death or LT of BA Cases
grouped into one period, resulting in a total of 7 periods. We also
divided all BA cases into 2 birth cohorts: an earlier cohort The percentage of death decreased from approximately
(19972004) and a later cohort (20052010). The frequency 70% in the early period to <20% in the most recent period
and incidences of hospitalization were calculated and compared (Table 1). A dramatic reduction of mortality was noted after
among the 7 periods and 2 cohorts. 2006 (decrease from 26.2% to 15.9%). However, the LT rate
remained approximately 30% among BA cases with Kasai
procedure. The overall percentage of no LT/death consequently
Statistical Analysis increased from 20% to approximately 60% (P < 0.001).
The data were analyzed by the 2-tailed Student t test for
continuous variables with a normal distribution, the Mann
Comparison Between the 2 Birth Cohorts
Whitney U test for continuous variables without a normal
distribution, and the x2 test for categorical variables. A Z-test As shown in Table 2, the later cohort (20052010) had
based on the Poisson regression was used to examine the significantly fewer hospitalization incidences than the earlier
incidences among 7 birth cohorts. Trends in the incidence of 1997 to 2004 cohort (5.0 vs 6.4, P < 0.001). The mortality was
BA patients were analyzed by the Cochrane-Armitage trend also significantly reduced from 47.8% to 21.2% (P < 0.001).
test. We used a Cox proportional hazards regression to estimate Therefore, the overall survival rate without LT/death increased
the relative risks for survival outcome (LT, death, and LT/death) from 31.6% to 56.4% (P < 0.001).
among BA patients. The analyses were adjusted for sex, calen-
dar year of birth (19972004 or 20052010), and age at the Selection of the Cutoff Value Based on the
Kasai procedure (>60 or 60 days). A receiver-operating ROC Curve
characteristic (ROC) curve was plotted to determine the optimal Based on the ROC curve, the optimal cutoff value for
cutoff values for the survival outcome (LT, death, and LT/death) Hosp/2yr as an indicator for LT was projected to be 5.5 times

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Medicine  Volume 95, Number 12, March 2016 SCC Reduce Hospitalization and Mortality of BA

TABLE 1. The Case Number, Incidence, Hospitalization, Length of Stay, Death, and Liver Transplant Rates of Biliary Atresia Cases
From 1997 to 2010

Year 19971998 19992000 20012002 20032004 20052006 20072008 20092010 P

BA case no. born in that 66 100 90 82 70 49 56


year
Birth no. 562,182 562,941 483,068 424,392 388,218 379,589 339,881
Incidence per 1000 births 0.12 0.18 0.19 0.19 0.18 0.13 0.16 0.682
Kasai operation, no. (%) 59 (89.4) 91 (91.0) 80 (88.9) 71 (86.6) 61 (87.1) 44 (89.8) 51 (91.1) 0.904
Among 457 BA cases s/p Kasai operation
Kasai operation age >60 d, 19 (32.2) 31 (34.1) 25 (31.3) 20 (28.2) 15 (24.6) 11 (25.0) 15 (29.4) 0.251
no. (%)
Kasai operation age, 65.9 (65.5) 57.1 (27.4) 51.8 (31.8) 67.5 (138.6) 50.7 (23.7) 46.9 (22.4) 46.4 (27.1) 0.100
average (SD)
Hospital no. per case until 2 6.9 (5.2) 6.3 (3.7) 6.0 (3.6) 6.6 (4.2) 5.0 (2.9) 5.3 (3.8) 4.9 (2.8) 0.001
y, average (SD)
LOS per hospital until 2 y, 87.4 (64.5) 87.0 (57.2) 83.8 (60.5) 88.6 (68.6) 86.4 (65.8) 76.6 (59.7) 81.1 (55.8) 0.432
average (SD)
Liver transplant, no. (%) 3 (5.1) 34 (37.4) 24 (30.0) 25 (35.2) 17 (27.9) 12 (27.3) 15 (29.4) 0.189
Death, no. (%) 41 (69.5) 50 (54.9) 33 (41.3) 20 (26.2) 16 (26.2) 7 (15.9) 10 (19.6) <0.001
Neither LT nor death, no. 16 (27.1) 17 (18.7) 30 (37.5) 32 (45.1) 33 (54.1) 26 (59.1) 29 (56.9) <0.001
(%)

P value, test for trend.


BA biliary atresia, LOS length of stay, LT liver transplantation, SD standard deviation.

per case, which yielded a sensitivity of 74.6% and a specificity Prediction Models for Major Outcomes of BA
of 64.8%, with an area under the curve (AUC) of 74.8% (95% Cases
confidence interval [CI] 69.2%77.9%; Appendix 1, http:// The Cox proportional hazards model results in Table 3
links.lww.com/MD/A832 and Figure 1). The AUC, sensitivity, shows that there was a 14% increase in risk for LT (hazard ratio
and specificity of Hosp/2yr as an indicator for death were not as [HR] 1.14, 95% CI 1.101.18) and a 5% increase in risk for
good as the values for LT, but they still reached significance death (HR 1.05, 95% CI 1.011.08) for each additional
(Appendix 1, http://links.lww.com/MD/A832). The combined hospitalization. The multivariate logistic regression model
model increased the specificity for either LT/death to 77.6%, results in Table 4 show that those cases with Hosp/2yr >6
with a sensitivity of 62.4%, and the AUC was 74.8% (95% CI: times had significantly higher risk for both LT (adjusted odds
70.4%79.3%; Appendix 1, http://links.lww.com/MD/A832 ratio [aOR] 4.35, 95% CI 2.826.73) and death
and Figure 1). Based on the ROC results, we chose 6 times (aOR 1.75, 95% CI 1.172.62). The later cohort (2005
as the cutoff value for Hosp/2yr to predict the probability or 2010) had a higher risk of LT, but a lower risk of death
final outcome. compared with the earlier cohort (19972004). The overall

TABLE 2. The Case Number, Incidence, Hospitalization, and Length of Stay of Biliary Atresia Cases From 1997 to 2010

Year 19972004 20052010 P Total

BA case no. born in that year 338 175 513


Incidence per 1000 births 0.17 0.16 0.582 0.16
Kasai operation, no. (%) 301 (89.1) 156 (89.1) 0.975 457 (89.1)
Among 457 cases with Kasai operation
Kasai operation age >60 d, no. (%) 95 (31.6) 41 (26.3) 0.242 136 (29.8)
Kasai operation age, average (SD) 59.9 (76.4) 48.2 (24.5) 0.064 55.88 (63.9)
Hospital no. per case until 2 y, average (SD) 6.4 (4.1) 5.0 (3.2) <0.001 5.94 (3.9)
LOS per hospital until 2 y, average (SD) 86.6 (61.9) 81.9 (60.7) 0.438 84.98 (61.5)
Liver transplant, no. (%) 86 (28.6) 44 (28.2) 0.934 130 (28.4)
Death, no. (%) 144 (47.8) 33 (21.2) <0.001 177 (38.7)
Neither LT nor death, no. (%) 95 (31.6) 88 (56.4) <0.001 183 (40.0)

P value, x2 test or t test, 1997 to 2004 versus 2005 to 2010.


BA biliary atresia, LOS length of stay, LT liver transplantation, SD standard deviation.

Copyright # 2016 Wolters Kluwer Health, Inc. All rights reserved. www.md-journal.com | 3
Lee et al Medicine  Volume 95, Number 12, March 2016

outcomes.10,12,17 For example, the Kasai procedure has


improved jaundice-free survival with the native liver at the
ages of 3 and 5 years.10,12 Therefore, it is reasonable to associate
the national implementation of the SCC screening program with
a reduction in the hospitalization rate of BA cases.
However, LT and death are the 2 BA case outcomes of
most concern. This population-based study further revealed that
the hospitalization rate was also significantly associated with
the survival outcome of BA cases. The multivariate logistic
regression model, which controlled for sex, age at the Kasai
procedure, and birth cohort, found that the hospitalization rate
was the most important factor associated with LT/death
(Table 4). A hospitalization frequency >6 times was associated
with a 6.32-fold increased risk of LT or death. Our hypothesis
FIGURE 1. The receiver-operating characteristic curve for predict- states that more hospitalizations indicate more complications,
ing the survival outcomes of LT, death, and LT or death in BA which can accelerate the development of liver cirrhosis and
cases after the Kasai procedure. BA biliary atresia, LT liver increase the need for LT. Following the reduction of the
transplantation. hospitalization rate since 2004, we have observed a large
reduction in mortality since 2006 (Table 1). Such a time lag
OR of LT/death was significantly reduced (OR 0.39, 95% is reasonable because death, naturally, occurs later than any
CI 0.250.59). Both multivariate regression models found other outcome.
that Hosp/2yr was significantly associated with a higher risk for Some may argue that it is nave to credit the improvement
LT/death after controlling for sex, age at the Kasai procedure, of final outcomes to the SCC screening program alone.
and birth cohort among BA cases. Although previous studies have documented the benefits of
the SCC screening program on increasing 3-month jaundice-
DISCUSSION free rates,10,12 the advantage of the SCC program on final
This was a 14-year nationwide population-based cohort outcomes of BA cases requires more evidence. Notably, this
study. We found a dramatic reduction in the hospitalization rate present study has observed a significant association between the
of BA cases after 2004, when the SCC program was fully hospitalization rate and mortality. As shown in Table 3, one
implemented in entire country. Throughout the study period, the additional hospitalization can increase the risk of LT and death
mortality rate was also significantly reduced, but the LT rate did by 14% and 5%, respectively. This result also reminded us that
not change. However, the overall survival rate, without LT or every hospitalization of BA cases is meaningful because of its
death, significantly improved. The multivariate analysis found potential effect on long-term survival outcome. We must ade-
the hospitalization rate was significantly associated with survi- quately care for BA cases in a timely manner and do our best to
val outcomes. An additional hospitalization increases the LT avoid any unnecessary hospitalizations.
and mortality rates by 14% and 5%, respectively. These data Finally, we evaluated the financial impact of this SCC
may provide valuable information for health professionals and screening program by comparing the direct medical costs of
families caring for BA cases. hospitalizations between 2 eras, before and after 2004. Con-
The SCC screening program has been confirmed to be a sidering the incidence of BA ranged 0.12 to 0.19 per 1000
sensitive and specific screening method for BA in infants.9,10 births, the annual cost saving of hospitalizations for BA cases
Universal screening using the SCC can enhance earlier referral, among 100,000 live births would be 80 to 120 thousand US
which may lead to timely performance of the Kasai procedure dollars (see Appendix 2, http://links.lww.com/MD/A832 for
in infants with BA and subsequently improved BA case calculation). Specially, this money just implies the direct

TABLE 3. Cox Proportional Hazards Models of Different Outcomes and Related Variables (Age, Sex, Birth Cohort, and
Hospitalization Rate)

Liver Transplantation Death Either Death or Liver Transplantation

HR (95% CI) HR (95% CI) HR (95% CI)

Age at Kasai operation


>60 vs 60 d 1.22 (0.841.75) 1.10 (0.801.51) 1.16 (0.901.50)
Sex
Male vs female 1.15 (0.811.62) 0.74 (0.551.00) 0.93 (0.731.18)
Hospitalization no. per case until 2 y
  
Per 1 time 1.14 (1.101.18) 1.05 (1.011.08) 1.11 (1.091.14)
Birth year

20052010 vs 19972004 1.70 (1.162.49) 0.55 (0.380.82) 0.89 (0.671.19)

CI confidence interval, HR hazard ratio.




P < 0.01.
P < 0.001.

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Medicine  Volume 95, Number 12, March 2016 SCC Reduce Hospitalization and Mortality of BA

TABLE 4. Multivariate Logistic Regression Analysis to Predict Liver Transplantation, Death, and Liver Transplantation or Death of
Biliary Atresia Patients

Liver Transplantation Death Either Death or Liver Transplantation


OR (95% CI) OR (95% CI) OR (95% CI)

Age at Kasai operation


>60 vs 60 d 1.32 (0.832.10) 1.19 (0.771.81) 1.32 (0.832.09)
Sex
Male vs female 1.10 (0.711.68) 0.69 (0.471.03) 0.82 (0.541.25)
Hospitalization no. per case until 2 y
  
>6 vs 6 times 4.35 (2.826.73) 1.75 (1.172.62) 6.32 (3.8810.29)
Birth year
 
20052010 vs 19972004 1.22 (0.771.93) 0.31 (0.200.48) 0.39 (0.250.59)

CI confidence interval, OR odds ratio.




P < 0.01.
P < 0.001.

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care for BA cases to the best of our abilities and avoid any and operation of biliary atresia in Taiwan: a 15-year population-
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by the ability to determine the real detection rate using this Screen. 2014;21:126132.
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can be affected by many factors such as the accessibility of for biliary atresia using infant stool color cards in Canada: Quebec
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